This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0).
License (http://creativecommons.org/licenses/by-nc-sa/4.0/) Advanced pancreatic cancer is com- monly associated with significant visceral pain, radiating in a belt-like distribution to the upper abdomen, referring to the lower back, and sig- nificantly affecting patients’ quality of life (QoL). The pain is often poorly controlled by pharmacotherapy, or the doses necessary to control the pain produce substantial adverse effects.
Other available pain management op- tions include invasive celiac plexus block or neurolysis, palliative radio- therapy, and systemic chemotherapy, all with limited efficacy. In this case re- port, we present the first non-invasive celiac plexus radiosurgery performed in Europe in a patient with pancreatic cancer, demonstrating that significant pain relief can be achieved through a non-invasive procedure performed within 2 outpatient visits.
Key words: radiosurgery, celiac plexus, pain, quality of life.
Contemp Oncol (Pozn) 2021; 25 (2): 140–145 DOI: https://doi.org/10.5114/wo.2021.107689
Noninvasive celiac plexus
radiosurgery in palliative treatment for patients with symptomatic
pancreatic cancer
Marcin Miszczyk1, Jerzy Wydmański2, Magdalena Kocot-Kępska3, Małgorzata Malec-Milewska4, Łukasz Dolla2, Wioletta Miśta2, Leszek Miszczyk2, Maoz Ben-Ailan5, Yaacov Richard Lawrence5
1IIIrd Department of Radiotherapy and Chemotherapy, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
2Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
3Department of Pain Research and Treatment, Jagiellonian University Medical College, Krakow, Poland
4Department of Anaesthesiology and Intensive Care, Medical Centre for Postgraduate Education, Warsaw, Poland
5Radiation Oncology, Sheba Medical Centre, Ramat Gan, Israel
Introduction
Although often referred to as the ‘silent killer’ due to its asymptomat- ic early presentation, pancreatic cancer is associated with pain in approxi- mately 75% of the patients at the time of diagnosis, and as much as 90% at the advanced stage [1]. Such pain is probably mediated through the celiac plexus [2] composed of 2 groups of ganglia located anteriorly and laterally to the aorta at the level of Th12 to L2 [3] vertebrae, which transmit the no- ciceptive input through splanchnic nerves and Th5-Th12 spinal nerve roots, and further through spinothalamic tracts to higher centres in the central nervous system [4].
The pancreatic ductal carcinoma, which constitutes up to 95% of pancre- atic cancers, has one of the highest incidences of perineural invasion among cancers (80–100%) [5], subsequently generating visceral pain with neuro- pathic component [6, 7]. Although relatively effective, the appropriate use of analgesics and co-analgesics according to the European Society for Medical Oncology guidelines [8] is not always sufficient for optimal pain control [5]
and is often associated with adverse effects related mostly to opioids [9].
Persistent pain not only significantly affects patients’ quality of life (QoL) [10] but also induces functional and structural changes at the peripheral, spinal, and supraspinal level of the nervous system, further facilitating and exacerbating the cancer-related pain through peripheral and central sensi- tization [11, 12].
According to the review by Vissers et al. [13], celiac plexus block (CPB), a transient interruption of pain transmission through local anaes- thetic injection, or celiac plexus neurolysis (CPN), a prolonged interruption through chemical ablation with alcohol [14], were found to significantly re- duce pain intensity and opioid consumption compared to systemic analge- sic therapy. However, these invasive methods do not remove the need for opioids and do not significantly improve the patients’ QoL [15]. In this case report, we explain the methodology and present the outcomes of the first patient in Europe to be treated with non-invasive celiac plexus radiosurgery, a novel approach towards combating visceral pain in patients with advanced pancreatic cancer.
Case report
Patient medical history
A 61-year-old male patient with advanced unresectable pancreatic cancer was referred by an anaesthesiologist to the radiotherapy (RT) department due to severe, de- bilitating pain, despite appropriate pharmacotherapy, and contraindications to CPB/CPN. The patient had had a pancreatic adenocarcinoma diagnosed 2 years earlier due to significant weight loss and abdominal pain. The tumour was found to be unresectable due to mesenteric vein and artery involvement. Gastroenteroanastomosis and cholecystoenterostomy were performed due to biliary and gastrointestinal obstruction, and the patient was referred for systemic treatment. The patient has been receiving chemotherapy consisting of FOLFOX, FOLFIRI, and once again FOLFIRI (ongoing) with 4- and 3-month breaks in between. Additionally, irreversible electroporation with calcium ions and chemotherapy, a novel modality of treatment in advanced pancreatic carcinoma [16], was performed less than a year after the primary diagnosis. At the time of registration, the patient had marker progression (CA 19 – 9 = 2143 U/mL), and a mildly enhancing lesion in the head of the pancreas described as a minor residual tumour on computed tomography (CT). The patient had never received RT before.
Baseline
The patient reported severe and stabbing pain, spread- ing from the upper abdomen to the lower back in a belt-like distribution. The general condition was modest, with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, and palliative performance scale (PPSv2) [17]
of 70%. The initial brief pain inventory – short form ques- tionnaire (BPI-SF) yielded an average 6/10 pain intensity, which ranged from 3/10 to 8/10, despite proper use of an- algesics. The remaining BPI-SF parameters (Table 1) and functional assessment of cancer therapy – hepatobiliary cancer questionnaire confirmed a significant impact of pain on QoL. At the time of registration, the patient was receiving a substantial amount of analgesics, including 75 μg/h transdermal fentanyl patch every 3 days, 20 mg immediate-release oral morphine twice a day along with
an average of four doses of 100 μg intranasal fentanyl dai- ly, 1g of metamizole thrice a day, and 150 mg of pregabalin twice a day. Due to the exceptionally long medical history of advanced, unresectable pancreatic cancer, low disease volume on CT, relatively young age, and no history of pri- or RT, we decided to initiate the treatment process with further diagnostics and performed a positron emission to- mography computed tomography (PET-CT) scan to assess the possibility of radical radiosurgery or radio-chemother- apy. Unfortunately, the PET-CT scan revealed significant disease advancement, a metabolically active 6 x 4.8 cm mass in the head of the pancreas, and a metastatic lymph node adjacent to the descending duodenum. The patient was subsequently consulted regarding ‘Celiac Plexus Ra- diosurgery for Pain Management’, and, having fulfilled all inclusion and exclusion criteria, he was enrolled in the clin- ical trial. To account for variability in pain reporting, the pa- tient had the assessment repeated before RT, which took place 2 weeks after the baseline assessment. The results were comparable to the initial assessment, as presented in Table 1.
Treatment preparation and delivery
The RT planning procedures started with the prepara- tion of an individual positioning device (vacuum mattress – Fig. 1 A), followed by a respiratory-gated deep inspiration breath hold (DIBH) treatment planning CT. The RT planning series are performed with the use of the aforementioned positioning device, to provide the best reproducibility of the patient’s anatomy during the treatment. The DIBH technique reduces the impact of internal organs’ respira- tory movement. The patient is asked to hold their breath multiple times during irradiation, and the respiratory cycle is supervised through external infrared optics monitoring a small plastic cube located on the patients’ chest, which can be seen in Figure 1 B.
The target volume for celiac plexus radiosurgery is de- fined anatomically as a 5 mm wide anterolateral aspect of the abdominal aorta at the level of Th12-L2 (Fig. 2). Due to the palliative intent of the treatment, the safety of RT delivery is our highest priority, and all of the organs at Fig. 1. Positioning device and the patients’ position on the treatment table
A B
142
contemporary oncologyrisk (OAR) are carefully contoured including the distal part of the oesophagus, stomach, bowel (including duodenal sub-volume), spinal cord, liver, and kidneys. To account for bowel movement, additional 0.5 and 1 cm margins are added, and derivate OARs are taken into account during RT planning.
The dose prescribed to the celiac plexus was a single fraction of 25 Gy. However, the dose distribution was significantly different from the usual uniform delivery of a single dose to the whole planning treatment volume (PTV). To account for the significant radiosensitivity of
the bowel adjacent to the celiac plexus, 4 separate vol- umes were defined and prescribed between 25 and 10 Gy (Fig. 3). This novel approach towards RT planning allows us to achieve delivery of a very high ablative dose to a rela- tively large volume (26.9 cc), and yet maintain high safety of the treatment.
On the day of the treatment, 2 hours before RT, the pa- tient received 8 mg of ondansetron, 8 mg of dexametha- sone, and 20 mg of omeprazole orally. The initial patient’s positioning was performed using two 2D kV images, fol- lowed by a respiratory-gated cone-beam CT (CBCT). The Fig. 2. Target definition for radiosurgical ablation of celiac plexus
Table 1. Analgesic consumption and quality of life-related brief pain inventory – short form parameters
2-weeks before RT Pre-treatment 3-weeks after RT 6-weeks after RT
Opioid consumption* 284 284 180 136
ECOG score 2 2 1 1
PPSv2 70% 70% 90% 80%
Brief pain inventory – short form
The patient is asked to describe the pain using a 0–10 scale, where 0 is no pain and 10 is a pain as bad as one can imagine
Pain at its worst in the last 24 h 8 7 1 0
Pain at its least in the last 24 h 3 4 0 0
Pain on average 6 5 1 2
Pain right now 7 5 0 0
The patient is asked to mark a number between 0 (no pain interference) and 10 (complete pain interference), which represents how the pain has interfered with the following aspects of life during the last 24 hours
General activity 7 5 0 0
Mood 6 7 0 1
Walking ability 6 6 0 0
Normal work 7 6 0 0
Relations with other people 7 6 0 0
Sleep 7 7 1 0
Enjoyment of life 6 6 1 0
*presented as oral morphine equivalent dose [mg]. The conversion factors used were 1 : 100 for fentanyl patch and 1 : 160 for intranasal fentanyl, RT – radiothera- py, ECOG – Eastern Cooperative Oncology Group, PPSv2 – palliative performance scale
patient’s position was aligned to the RT planning CT (Fig. 4), and irradiation was initiated. The whole therapeutic ses- sion took about 30 minutes, including positioning.
Results
Immediately after treatment, the patient experi- enced transient pain exacerbation of up to 8 points on an 11-point numerical rating scale (NRS), mild diarrhoea, and fatigue. The adverse effects peaked on the second day and slowly decreased. At 1 week, the patient re- ported persistent fatigue and mild diarrhoea, but the pain was reduced to an average NRS of 4. By the second week, the adverse effects subsided. At 3 weeks, the pain was optimally controlled (Table 1) using only a 75 μg/h transdermal fentanyl patch, and the patient was no lon- ger using short-acting analgesics, neuropathic agents, or metamizole. The total oral morphine equivalent dose (MED) consumption of analgesics dropped by 37% to a MED of 180 mg, and performance status improved to 1 and 90% on the ECOG and PPSv2 scale, respectively. We advised further reduction of opioids, and at 6 weeks the patient was using a 50 μg/h transdermal fentanyl patch,
Fig. 3. Dose distribution in the target volume, illustrating the use of dose-painting to avoid overdosing the small bowel. Colours closer to red represent a higher dose
with no significant cancer-related pain, and little effect of pain on QoL aspects (Table 1). The patient, however, reported episodes of breakthrough pain every few days, which required an application of a single dose of 100 μg of intranasal fentanyl, up to a total MED of 136 mg. He also noticed episodes of heartburn and discomfort in the right hip, which were probably unrelated to cancer. The clinical situation remained stable until the control visit at 3 months after the treatment, when the patient reported a partial relapse of symptoms and increased pain inten- sity up to 4/10, which required a subsequent increase of analgesic dose and use of short-acting opioids.
The patient was eventually disqualified from further systemic treatment due to deteriorating blood tests, and at 5 months after treatment a CT revealed significant dis- ease progression. The progression led to significant pain and functional status decline. The last available informa- tion regarding the patient was obtained at 22 weeks af- ter treatment, through a phone call with the family. The patient was spending about 23.5 hours a day in bed, had reduced fluid and food intake, and was receiving a dose of analgesics comparable to the pre-treatment period.
144
contemporary oncologyFig. 4. Patient’s positioning on the treatment couch. The images show photos of the actual treatment console on the day of treatment, pre- senting cone-beam computed tomography matched with the treatment planning computed tomography as it was approved for treatment by the attending physician
Discussion
To our best knowledge, in this article, we present the case report of the first patient treated for pain with celiac plexus radiosurgery in Europe. However; this method of treatment was developed at the Sheba Medical Centre, Israel. The initial proof-of-concept trial, which included 21 patients treated with either 5 x 9 Gy (9.5%) or a single fraction of 25 Gy (90.5%), resulted in pain reduction in all cases, in- cluding 7 (33.3%) patients reporting complete pain relief.
The median baseline pain of 6/10 was reduced to 2.3/10 at 3 weeks, and 1.8/10 at 6 weeks (p < 0.0005) [18]. Moreover, the treatment provided a QoL improvement, including a sta- tistically significant decrease in all domains of pain-interfer- ence [19]. As a consequence of positive results, the currently ongoing international phase II trial was initiated [20].
Celiac plexus radiosurgery can be applied both as an upfront palliative procedure or in patients refracto- ry to CPD/CPN [21]. Considering the lack of necessity for hospitalization, the treatment can be completed within 1–2 weeks of the initial registration visit, and its availabil- ity remains uncompromised by the in-patient restrictions related to the COVID-19 pandemic.
The safety of celiac plexus radiosurgery is yet to be established in the context of re-irradiation, and for now, the previous RT to the upper abdomen is considered to be a contraindication. Nonetheless, the protocol allows for the simultaneous treatment of the primary tumour at the primary doctors’ discretion, usually to a single dose of 10–15 Gy.
Fractionated palliative RT has previously been reported to cause pain relief in advanced pancreatic cancer patients [22–25], but the data is of relatively low quality due to the retrospective nature of the reports, heterogenous study groups, and significant variability in applied RT fraction- ation schemes. Nevertheless, such treatment remains an option in patients who are not candidates for CPR.
Conclusions
Celiac plexus radiosurgery has the potential to provide significant pain relief along with an improvement in QoL in advanced pancreatic cancer patients. The results of the ongoing international prospective trial (NCT03323489) are necessary to confirm its efficacy and safety.
Acknowledgments
The patient was treated within the clinical trial de- signed and led by Dr. Yaacov Lawrence (ClinicalTrials.gov database identifier NCT03323489). Ethical approval was obtained in December 2019 at Maria Skłodowska-Curie National Research Institute Of Oncology under the signa- ture of KB/430-107/19.
This work is supported by “Gateway for Cancer Re- search” (G-17-100), and the “Israel Cancer Association”
through a donation from Irma and Simon Gross.
The authors declare no conflict of interest.
References
1. Yan BM, Myers RP. Neurolytic celiac plexus block for pain control in unresectable pancreatic cancer. Am J Gastroenterol 2007; 102:
430-438.
2. Leppert W, Zajaczkowska R, Wordliczek, J et al. Pathophysiology and clinical characteristics of pain in most common locations in cancer patients. J Physiol Pharmacol 2016; 67: 787-799.
3. Penman ID. Coeliac plexus neurolysis. Best Pract Res Clin Gastro- enterol 2009; 23: 761-766.
4. Bulmer D, Roza C. The Oxford Handbook of the Neurobiology of Pain. Oxford University Press, Oxford 2020.
5. Bapat AA, Hostetter G, von Hoff DD, Han H. Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer 2011;
11: 695-707.
6. Ceyhan GO, Schäfer KH, Kerscher AG, et al. Nerve growth factor and artemin are paracrine mediators of pancreatic neuropathy in pancreatic adenocarcinoma. Ann Surg 2010; 251: 923-931.
7. Demir IE, Ceyhan GO, Rauch U, et al. The microenvironment in chronic pancreatitis and pancreatic cancer induces neuronal plas- ticity. Neurogastroenterol Motil 2010; 22: 480-490.
8. Fallon M, Giusti R, Aielli F, et al. Management of cancer pain in adult patients: ESMO clinical practice guidelines. Ann Oncol 2018;
29: iv166-iv191.
9. Carter GT, Duong V, Ho S, et al. Side effects of commonly pre- scribed analgesic medications. Phys Med Rehabil Clin N Am 2014;
25: 457-470.
10. Kelsen DP, Portenoy RK, Thaler HT, et al. Pain and depression in patients with newly diagnosed pancreas cancer. J Clin Oncol 1995;
13: 748-755.
11. Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP. Molecular mech- anisms of cancer pain. Nat Rev Cancer 2002; 2: 201-209.
12. Wordliczek J, Zajączkowska R. Mechanisms in cancer pain. Cancer Pain, Springer-Verlag London Ltd, London 2013: 47-70.
13. Vissers KCP, Besse K, Wagemans M, et al. 23.Pain in patients with cancer. Pain Pract 2011; 11: 453-475.
14. Hameed M, Hameed H, Erdek M. Pain management in pancreatic cancer. Cancers (Basel) 2011; 3: 43-60.
15. Wong GY, Schroeder DR, Carns PE, et al. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled tri- al. J Am Med Assoc 2004; 291: 1092-1099.
16. Rudno-Rudzińska J, Kielan W, Guziński M, et al. The first study of irreversible electroporation with calcium ions and chemotherapy in patients with locally advanced pancreatic adenocarcinoma.
Appl Sci 2020; 10: 5163.
17. Q&A Manual, Instructions & Definitions for Use of Palliative Per- formance Scale (PPSv2). [https://victoriahospice.org/wp-content/
uploads/2020/08/PPSv2-QA-Instructions-and-Definitions-updat- ed-July-2020.pdf].
18. Lawrence YR, Hammer L, Morag O, et al. Celiac plexus radiosur- gery: a new palliative modality for upper gastrointestinal malig- nancies – final results of a proof-of-concept clinical trial. J Clin Oncol 2018; 36: 10098-10098.
19. Lawrence YR, Hammer L, Morag O, et al. Abstract CT147: celiac plexus radiosurgery a new palliative modality for upper gastroin- testinal malignancies – final quality of life results from a proof-of- concept clinical trial. Cancer Res 2019; 79: CT147-CT147.
20. Lawrence YR, Meron T, Dicker AP, et al. Celiac plexus radiosurgery for pain management in advanced cancer patients: an interna- tional phase II trial. J Clin Oncol 2019; 37: TPS466-TPS466.
21. Celiac plexus radio-surgery for pain management - full text view - clinicaltrials.gov. [https://clinicaltrials.gov/ct2/show/
NCT03323489].
22. Morganti AG, Trodella L, Valentini V, et al. Pain relief with short term irradiation in locally advanced carcinoma of the pancreas.
J Palliat Care 2003; 19: 258-262.
23. Ebrahimi G, Rasch CRN, van Tienhoven G. Pain relief after a short course of palliative radiotherapy in pancreatic cancer, the Aca- demic Medical Center (AMC) experience. Acta Oncol (Madr) 2018;
57: 697-700.
24. Wolny-Rokicka E, Sutkowski K, Grządziel A, et al. Tolerance and efficacy of palliative radiotherapy for advanced pancreatic cancer:
a retrospective analysis of single-institutional experiences. Mol Clin Oncol 2016; 4: 1088-1092.
25. Tian Q, Zhang F, Wang Y. Clinical assessment of palliative radio- therapy for pancreatic cancer. Cancer Radiother 2018; 22: 778-783.
Address for correspondence Marcin Miszczyk
IIIrd Department of Radiotherapy and Chemotherapy
Maria Sklodowska-Curie National Research Institute of Oncology 15 Wybrzeże Armii Krajowej
44-102, Gliwice, Poland
e-mail: marcin.miszczyk@io.gliwice.pl Submitted: 21.03.2021
Accepted: 24.04.2021
